title: Benzenesulfonamides with pyrimidine moiety as inhibitors of human carbonic anhydrases I, II, VI, VII, XII, and XIII.
abstract: Two groups of benzenesulfonamide derivatives, bearing pyrimidine moieties, were designed and synthesized as inhibitors of carbonic anhydrases (CA). Their binding affinities to six recombinant human CA isoforms I, II, VI, VII, XII, and XIII were determined by the thermal shift assay (TSA). The binding of several inhibitors was measured by isothermal titration calorimetry (ITC). Direct demonstration of compound inhibition was achieved by determining the inhibition constant by stopped-flow CO2 hydration assay. The most potent compounds demonstrated selectivity towards isoform I and affinities of 0.5 nM. The crystal structures of selected compounds in complex with CA II, XII, and XIII were determined to atomic resolution. Compounds described here were compared with previously published pyrimidinebenzenesulfonamides.(1) Systematic structure-activity analysis of 40 compound interactions with six isoforms yields clues for the design of compounds with greater affinities and selectivities towards target CA isoforms.
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius LT-02241, Lithuania.
authors.forename: Edita
authors.initials: E
authors.lastname: Čapkauskaitė
authors.forename: Asta
authors.initials: A
authors.lastname: Zubrienė
authors.forename: Alexey
authors.initials: A
authors.lastname: Smirnov
authors.forename: Jolanta
authors.initials: J
authors.lastname: Torresan
authors.forename: Miglė
authors.initials: M
authors.lastname: Kišonaitė
authors.forename: Justina
authors.initials: J
authors.lastname: Kazokaitė
authors.forename: Joana
authors.initials: J
authors.lastname: Gylytė
authors.forename: Vilma
authors.initials: V
authors.lastname: Michailovienė
authors.forename: Vaida
authors.initials: V
authors.lastname: Jogaitė
authors.forename: Elena
authors.initials: E
authors.lastname: Manakova
authors.forename: Saulius
authors.initials: S
authors.lastname: Gražulis
authors.forename: Sigitas
authors.initials: S
authors.lastname: Tumkevičius
authors.forename: Daumantas
authors.initials: D
authors.lastname: Matulis
mesh_terms: D001665:Binding Sites; D002151:Calorimetry; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D007527:Isoenzymes; D011743:Pyrimidines; D011994:Recombinant Proteins; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C030986:pyrimidine
keywords: Carbonic anhydrase isozymes; Isothermal titration calorimetry; Pyrimidine; Sulfonamides as CA inhibitors; Thermal shift assay; ThermoFluor®